Insulin Solution Stability and Biocompatibility with Materials Used for an Implantable Insulin Delivery Device Using Reverse Phase HPLC Methods

open access articleAbstract: Insulin (Humulin® R IU500) has been delivered from an implantable artificial pancreas in diabetic rats and pigs. The artificial pancreas which was implanted in the peritoneum was fabricated from several biocompatible materials such as polycarbonate, stainless steel, polyurethane, titanium and a polyurethane resin. The device also contains a glucose responsive smart gel which controls the di usion of insulin dependent on the surrounding glucose environment. As the insulin reservoir is refillable and in contact with the device materials, assessing its biocompatibility with these various device component materials was conducted. Insulin can undergo chemical degradation mainly via a deamidation reaction on glutamine and asparagine residues rendering its biological hormone functionality. Two Reverse Phase High Performance Liquid Chromatography (RP-HPLC) methods were developed and validated for detection of insulin and degradant Asn A21 desamido insulin (method A) and insulin and degradant Asn B3 desamido insulin (method B). Material biocompatibility studies show that stainless steel and titanium are suitable for an implantable insulin delivery device design over a 31-day period. The use of polycarbonate and polyurethane could be considered if the insulin reservoir in the device was only to remain in the device for less than 11 days after which time there is a loss in cresol which acts in a protective capacity for insulin stability

Pharmacology based toxicity assessment : towards quantitative risk prediction in humans

This thesis focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is proposed to 1) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; 2) facilitate the integration of historical evidence and thereby the translation of findings across species; and 3) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Nonlinear-mixed effects modelling is recommended as a tool to account for such requirements. Our goal was to explore the feasibility of a model-based approach to toxicology assessment and risk prediction in humans and, where possible, to compare the performance of this approach to traditional safety assessment approaches. The investigational plan of the thesis was divided into two sections where the development of methodology is followed by a case study with real data. A variety of analysis strategies and protocol designs are investigated where we set the constraint that proposals to deviate from existing protocols be minimal. We finally compile recommendations for protocol optimisation and data analysis/interpretation strategies to facilitate the implementation of model-based techniques in safety pharmacology and toxicology researchUBL - phd migration 201

Manipulations of egg-gallery length to vary brood density in spruce beetle, Dendroctonus rufipennis (Coleoptera: Scolytidae): Effects on brood survival and quality

Different brood densities were produced under a constant bark surface area of the spruce host, by excising egg-producing female <i>Dendroctonus rufipennis</i> from the host material after they had excavated galleries of specified lengths. This procedure allowed a constant attack density. The numbers of adult progeny produced/cm of egg-gallery were significantly greater from bark slabs with short galleries and low densities: the sizes (pronotal widths) of adult progeny of both sexes were also significantly greater from low than from high densities; and the distribution patterns of chromatin differed significantly among high, medium and low densities

Glucose lowering strategies with insulin

open access journalPeople with type 1 diabetes must use insulin and a large fraction of those with type 2 condition also do so. Many therefore struggle with the unpredictable balancing of insulin dose with calorie intake and utility. A healthy pancreas makes meticulous adjustment on a continuous basis that present therapeutic insulin administration cannot match. However, much progress has been made to make it simpler to inject both background and fast-acting boost insulins with a view to better mimicking normal pancreatic output. The present fast insulins are reviewed with accent on the primary amino acid structures of the biosynthetic types that diffuse more quickly than regular insulin that associates in hexamers. This makes boost doses kinetically and clinically more effective, allowing people to inject better estimated boost and corrective doses. Formulation advances are discussed for their present and potential contributions. The newer slow-acting insulins are also described and compared, their advantage also being kinetic with a lower likelihood of inducing overnight hypoglycaemia when used optimally. Finally, the appreciation of the advantages of alternative routes of administration such as oral and peritoneal are included in this review because of the possibility of altering the hepatic to peripheral ratio, the reasons for which are more effective but less obesogenic insulin activity. The logistics of oral insulin are summarised in terms of the risks to the insulin structure, the facilitation of paracellular uptake at the apical surface and the paradoxically advantageous hepatic first pass. Other non-invasive routes are also included in the review

The Nottingham Spinal Health (NoSH) Study: a cohort study of patients hospitalised with vertebral fragility fractures

© 2019, The Author(s). Summary: Patients hospitalised with vertebral fragility fractures were elderly, multimorbid and frail and lead to poor outcomes. Their hospital treatment needs to consider this alongside their acute fracture. A systematic organised model of care, such as an adaptation of orthogeriatric hip fracture care, will offer a more holistic approach potentially improving their outcomes. Purpose: Patients admitted to hospital with vertebral fragility fractures are elderly and have complex care needs who may benefit from specialist multidisciplinary input. To date, their characteristics and outcomes have not been reported sufficiently. This study aims to justify such a service. Methods: Patients admitted with an acute vertebral fragility fracture over 12 months were prospectively recruited from a university hospital in England. Data were collected soon after their admission, at discharge from hospital and 6 months after their hospital discharge on their characteristics, pain, physical functioning, and clinical outcomes. Results: Data from 90 participants were analysed. They were mainly elderly (mean age 79.7 years), multimorbid (69% had ≥ 3 comorbid condition), frail (56% had a Clinical Frailty Scale score ≥ 5), cognitively impaired (54% had a MoCA score of < 23) and at high risk of falls (65% had fallen ≥ 2 in the previous year). Eighteen percent died at 6 months. At 6 months post-hospital discharge, 12% required a new care home admission, 37% still reported their pain to be severe and physical functioning was worse compared with their preadmission state. Conclusion: Patients hospitalised with vertebral fragility fractures were elderly, multimorbid, frail and are susceptible to persistent pain and disability. Their treatment in hospital needs to consider this alongside their acute fracture. A systematic organised model of care, such as an adaptation of orthogeriatric hip fracture care, will offer a more holistic approach potentially improving their outcomes

Manipulations of egg-gallery length to vary brood density in spruce beetle, Dendroctonus rufipennis (Coleoptera: Scolytidae): Effects on brood survival and quality

Different brood densities were produced under a constant bark surface area of the spruce host, by excising egg-producing female Dendroctonus rufipennis from the host material after they had excavated galleries of specified lengths. This procedure allowed a constant attack density. The numbers of adult progeny produced/cm of egg-gallery were significantly greater from bark slabs with short galleries and low densities: the sizes (pronotal widths) of adult progeny of both sexes were also significantly greater from low than from high densities; and the distribution patterns of chromatin differed significantly among high, medium and low densities

Thermoresponsive Gels

An invited review and relates to the responsive gel used in the "artificial pancreas" work og INsmart, DMU. This article is an Open Access journal.Thermoresponsive gelling materials constructed from natural and synthetic polymers can be used to provide triggered action and therefore customised products such as drug delivery and regenerative medicine types as well as for other industries. Some materials give Arrhenius-type viscosity changes based on coil to globule transitions. Others produce more counterintuitive responses to temperature change because of agglomeration induced by enthalpic or entropic drivers. Extensive covalent crosslinking superimposes complexity of response and the upper and lower critical solution temperatures can translate to critical volume temperatures for these swellable but insoluble gels. Their structure and volume response confer advantages for actuation though they lack robustness. Dynamic covalent bonding has created an intermediate category where shape moulding and self-healing variants are useful for several platforms. Developing synthesis methodology—for example, Reversible Addition Fragmentation chain Transfer (RAFT) and Atomic Transfer Radical Polymerisation (ATRP)—provides an almost infinite range of materials that can be used for many of these gelling systems. For those that self-assemble into micelle systems that can gel, the upper and lower critical solution temperatures (UCST and LCST) are analogous to those for simpler dispersible polymers. However, the tuned hydrophobic-hydrophilic balance plus the introduction of additional pH-sensitivity and, for instance, thermochromic response, open the potential for coupled mechanisms to create complex drug targeting effects at the cellular level

Cardiometabolic Health Among Adult Offspring of Hypertensive Pregnancies: The Cardiovascular Risk in Young Finns Study.

BACKGROUND: Cardiometabolic health among adult offspring of hypertensive disorders of pregnancy (HDP) is relatively unknown. We hypothesized that offspring of HDP would have abnormalities in the retinal microvasculature and cardiac structure by midadulthood. METHODS AND RESULTS: The Cardiovascular Risk in Young Finns Study included randomly selected children from 5 Finnish university cities. The mean age of participants was 40 years (range 34-49 years) at the time of retinal photography and cardiac assessment. Offspring born ≥37 weeks of gestation and appropriate for gestational age (n=1006) were included. Offspring of HDP had higher systolic blood pressure (β=4.68, P<0.001), body mass index (β=1.25, P=0.009), and waist circumference (β=0.25, P=0.042), compared with offspring of normotensive pregnancies. However, no differences in fasting glucose, insulin, lipid profile, carotid intima media thickness, or brachial artery flow-mediated dilatation were shown. Retinal arteriolar diameters were narrower (β=-0.43, P=0.009) and longer (β=32.5, P=0.023) and the arteriolar length-to-diameter ratio was higher (β=2.32, P=0.006) among offspring of HDP, after adjustment for age and sex. Left atrial volume indexed to body surface area (β=1.34, P=0.040) was increased. Adjustment for the confounding effects of birth weight, body mass index, smoking and socioeconomic status, and the mediating effect of hypertension had little impact on the associations. CONCLUSIONS: Abnormalities of the retinal microvasculature and cardiac structure are seen in offspring of HDP in midadulthood. These findings may need to be considered in future primary prevention strategies of cardiovascular disease among offspring of HDP

How children eat may contribute to rising levels of obesity children's eating behaviours: An intergenerational study of family influences

The term ‘obesogenic environment’ is rapidly becoming part of common phraseology. However, the influence of the family and the home environment on children's eating behaviours is little understood. Research that explores the impact of this micro environment and intergenerational influences affecting children's eating behaviours is long overdue. A qualitative, grounded theory approach, incorporating focus groups and semi-structured interviews, was used to investigate the family environment and specifically, the food culture of different generations within families. What emerged was a substantive theory based on ‘ordering of eating’ that explains differences in eating behaviours within and between families. Whereas at one time family eating was highly ordered and structured, typified by the grandparent generation, nowadays family eating behaviours are more haphazard and less ordered, evidenced by the way the current generation of children eat. Most importantly, in families with an obese child eating is less ordered compared with those families with a normal weight child. Ordering of eating' is a unique concept to emerge. It shows that an understanding of the eating process is crucial to the development and improvement of interventions targeted at addressing childhood obesity within the family context

Acceptability of bisphosphonates among patients, clinicians and managers: a systematic review and framework synthesis

Objective: To explore the acceptability of different bisphosphonate regimens for the treatment of osteoporosis among patients, clinicians and managers, payers and academics. Design: A systematic review of primary qualitative studies. Seven databases were searched from inception to July 2019. Screening, data extraction and quality assessment of full-articles selected for inclusion were performed independently by two authors. A framework synthesis was applied to extracted data based on the theoretical framework of acceptability (TFA). The TFA includes seven domains relating to sense-making, emotions, opportunity costs, burden, perceived effectiveness, ethicality and self-efficacy. Confidence in synthesis findings was assessed. Setting: Any developed country healthcare setting. Participants: Patients, healthcare professionals, managers, payers and academics. Intervention: Experiences and views of oral and intravenous bisphosphonates. Results: Twenty-five studies were included, mostly describing perceptions of oral bisphosphonates. We identified, with high confidence, how patients and healthcare professionals make sense (coherence) of bisphosphonates by balancing perceptions of need against concerns, how uncertainty prevails about bisphosphonate perceived effectiveness and a number of individual and service factors that have potential to increase self-efficacy in recommending and adhering to bisphosphonates. We identified, with moderate confidence, that bisphosphonate taking induces concern, but has the potential to engender reassurance, and that both side effects and special instructions for taking oral bisphosphonates can result in treatment burden. Finally, we identified with low confidence that multimorbidity plays a role in people’s perception of bisphosphonate acceptability. Conclusion: By using the lens of acceptability, our findings demonstrate with high confidence that a theoretically informed, whole-system approach is necessary to both understand and improve adherence. Clinicians and patients need supporting to understand the need for bisphosphonates, and clinicians need to clarify to patients what constitutes bisphosphonate treatment success. Further research is needed to explore perspectives of male patients and those with multimorbidity receiving bisphosphonates, and patients receiving intravenous treatment